Every year, close to one million new cases of lung cancer (LC) are diagnosed. In the USA, it is estimated that approximately 213,000 new cases were identified in 2007 (American Cancer Society). Within two years of diagnosis, most of these patients (~160,000) will die. The diagnosis of this disease is usually subsequent to routine chest X-ray and/or CT and MRI and is confirmed upon biopsy and functional (fluorine-18-labeled deoxyglucose) PET imaging. Treatment of lung cancer can involve a combination of surgery, chemotherapy, and radiation therapy as well as newer experimental methods. However, the five-year survival rate of patients with lung cancer is approximately 15% and has not changed over the past several decades. Thus, it is imperative to develop highly specific, sensitive, and accurate methods for screening and early detection of occult disease. Tumors originate from normal cells upon the accumulation of genetic and epigenetic alterations. These transformed cells acquire new "cancer-specific" molecular fingerprints (DNA/RNA/protein/lipid) that give them unique phenotypes. We postulate that the false-positive and false-negative rates obtained in various blood-based, tumor-specific-signature assays are a consequence of the same Achilles'heel: they all depend on population-derived average signature profiles obtained from the blood of "healthy" controls, i.e. the baseline/background signature(s) is/are NOT specific to the genetic makeup of the individual being tested. In this application, we propose to (i) develop a highly innovative WBC-based assay that (a) will accurately predict the presence of primary and/or metastatic LC lesions in an animal, and (b) is independent of population-derived average signatures of "healthy" controls;and (ii) examine the capacity of the assay to detect the response of tumors to therapy as well as the presence of LC in animals before the tumors are diagnosed by external imaging modalities. We anticipate that the WBC-based blood assay eventually will (i) be useful in the detection of occult lung tumors with high specificity, sensitivity, and accuracy;(ii) enable the early diagnosis of tumor presence in individuals who are not known to have the disease or who have recurrent disease;(iii) move meaningful intervention to a much earlier position on the path of tumor progression, thereby forestalling the development of metastatic disease;(iv) monitor the response of tumors to routine (e.g., surgery, chemotherapy) and experimental treatment(s);and (v) allow tumor detection, diagnosis, and treatment to be closely coupled (i.e., personalization of LC therapy).